Topical anesthetics

ABSTRACT

The present disclosure provides compounds useful as anesthetics, such as topical anesthetics, of general formula (VI):wherein:R1 is H, Cl, F, —CF3, —OCF3, —OMe, or methyl;R8 is selected from the group consisting of:—NH2, —N(H)Alk, —N(Alk)2,R7 is H or alkyl;m is 3 to 6;p is 1 to 4;q is 1 to 4;p+q is 3 to 6; andeach Alk is independently an aliphatic carbon group consisting of 1 to 6 carbon atoms,and methods of making and using same.

PRIORITY CLAIM

This application is a divisional application of U.S. patent application Ser. No. 17/689,827, filed on Mar. 8, 2022, which claims priority to U.S. Provisional Patent Application Ser. No. 63/317,868, filed Mar. 8, 2022, the entire contents of each of which are incorporated herein by reference and relied upon.

FIELD

The present disclosure provides compounds useful as anesthetic agents methods of making same, compositions comprising same, and methods of treating or preventing pain using same.

BACKGROUND

Anesthetic agents are commonly used to treat or prevent pain sensations. However, certain classes of anesthetics encourage overuse, abuse, and/or overprescribing. Other agents are potent, but provide low bioavailability for example when administered topically.

A need persists for improved anesthetic agents, especially agents that are effective when applied topically to skin of a subject.

SUMMARY

In one embodiment, the present disclosure provides a compound of formula (I):

wherein:

-   -   R₁ is H, —OMe, Me, or one or more electron withdrawing groups;     -   R₂ and R₃ are each independently H or alkyl or, taken together,         form a 4- to 8-membered heterocyclic ring with the adjacent         nitrogen atom;     -   R₄ is H or alkyl;     -   R₅ is H or one or more electron donating groups; and     -   n is 1 to 4.

In other embodiments, the present disclosure provides a compound of formula (II):

wherein:

-   -   EWG is one or more electron withdrawing groups selected from the         group consisting of: Cl, F, CF₃, and OCF₃;     -   R₂ and R₃ are each independently H or alkyl;     -   Alk is an aliphatic carbon group consisting of 1 to 6 carbon         atoms; and     -   EDG is one or more alkoxy or alkyl electron donating groups.

In other embodiments, the present disclosure provides a compound of formula (III):

wherein:

-   -   EWG is one or more electron withdrawing groups selected from the         group consisting of: Cl, F, CF₃, and OCF₃;     -   R₈ is selected from the group consisting of:         -   —NH₂, —N(H)Alk, —N(Alk)₂,

-   -   R₇ is H or alkyl;     -   m is 3 to 6;     -   p is 1 to 4;     -   q is 1 to 4;     -   p+q is 3 to 6;     -   each Alk is independently an aliphatic carbon group consisting         of 1 to 6 carbon atoms; and     -   EDG is one or more alkoxy or alkyl electron donating groups.

In other embodiments, the present disclosure provides a compound of formula (IV):

wherein:

-   -   R₁ is H, Cl, F, —CF₃, —OCF₃, or —OMe;     -   R₈ is selected from the group consisting of:         -   —NH₂, —N(H)Alk, —N(Alk)₂,

-   -   R₇ is H or alkyl;     -   m is 3 to 6;     -   p is 1 to 4;     -   q is 1 to 4;     -   p+q is 3 to 6;     -   each Alk is independently an aliphatic carbon group consisting         of 1 to 6 carbon atoms; and     -   EDG is one or more amino, aryl, acylamido, acyloxy, alkoxy or         alkyl electron donating groups.

In other embodiments, the present disclosure provides a compound of formula (V):

wherein:

-   -   R₁ is H, Cl, F, —CF₃, —OCF₃, or —OMe;     -   R₈ is selected from the group consisting of:         -   —NH₂, —N(H)Alk, —N(Alk)₂,

-   -   R₇ is H or alkyl;     -   m is 3 to 6;     -   p is 1 to 4;     -   q is 1 to 4;     -   p+q is 3 to 6; and     -   each Alk is independently an aliphatic carbon group consisting         of 1 to 6 carbon atoms.

In other embodiments, the present disclosure provides a compound of formula (VI):

wherein:

-   -   R₁ is H, Cl, F, —CF₃, —OCF₃, —OMe, or methyl;     -   R₈ is selected from the group consisting of:         -   —NH₂, —N(H)Alk, —N(Alk)₂,

-   -   R₇ is H or alkyl;     -   m is 3 to 6;     -   p is 1 to 4;     -   q is 1 to 4;     -   p+q is 3 to 6; and     -   each Alk is independently an aliphatic carbon group consisting         of 1 to 6 carbon atoms.

In other embodiments, the present disclosure provides a compound of formula (VII):

wherein:

-   -   R_(1a) is H, Cl, F, —CF₃, —OMe, or methyl;     -   R_(1b) is H, Cl, F, —CF₃, or —OCF₃;     -   R_(1c) is H, Cl, F, or —OMe;     -   R_(1d) is H, Cl, F, —CF₃, or —OCF₃;     -   R_(1e) is H, Cl, F, —CF₃, —OMe, or methyl;     -   R₂ and R₃ are each independently H or alkyl or, taken together,         form a 4- to 8-membered heterocyclic ring with the adjacent         nitrogen atom;     -   R₄ is H or alkyl; and     -   R₅ is H or one or more electron donating groups.

In other embodiments, the present disclosure provides a composition comprising a compound of any one of formulas (I) to (VII).

In other embodiments, the present disclosure provides a method of treating or preventing pain in a subject, the method comprising topically applying the composition comprising a compound of any one of formulas (I) to (VII) to skin of the subject proximal to perceived pain or expected pain.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a representative synthetic route for producing compounds of formula (I).

FIG. 2 shows a representative synthetic route for producing compounds of formula (II).

FIG. 3 shows a representative synthetic route for producing compounds of formula (II).

FIG. 4 shows a representative synthetic route for producing compounds of formula (IV).

FIG. 5 shows a representative synthetic route for producing compounds of formula (V).

FIG. 6 shows a representative synthetic route for producing compounds of formula (VI).

FIG. 7 shows a representative synthetic route for producing compounds of formula (VII).

DETAILED DESCRIPTION

The present disclosure provides compounds useful as anesthetic agents, for example to treat or prevent pain when applied topically to skin of a subject, and methods of making such compounds and using such compounds to treat or prevent pain.

1. Anesthetic Compounds

The present disclosure provides compounds of formula (I):

wherein:

-   -   R₁ is H, alkyl, alkoxy, or one or more electron withdrawing         groups;     -   R₂ and R₃ are each independently H or alkyl or, taken together,         form a 4- to 8-membered heterocyclic ring with the adjacent         nitrogen atom;     -   R₄ is H or alkyl;     -   R₅ is H or one or more electron donating groups; and     -   n is 1 to 4.

The present disclosure also provides salts of compounds of formula (I), which may be prepared for example by contacting a neutral compound of formula (I) with an acid (e.g., hydrochloric acid) to form a salt (e.g., a hydrochloride salt) of the compound of formula (I). A suitable salt of a compound of formula (I) is a salt of a mineral or organic acid. Suitable mineral acids include hydrochloric, hydrobromic, hydroiodic, nitric or sulfuric acid. A suitable organic acid is, for example, an organic achiral acid such as acetic, trifluoroacetic, oxalic or p-toluenesulfonic acid, or an organic chiral acid such as L-tartaric acid, dibenzoyl-L-tartaric acid or di-p-toluoyl-L-tartaric acid.

The present disclosure also provides hydrates of compounds of formula (I).

In some embodiments, R₁ is selected from the group consisting of: H, alkyl, alkoxy, and electron withdrawing groups. In some embodiments, only one R₁ group is present and may be at the ortho-, meta-, or para-position of the aryl ring. In other embodiments, two to five R₁ groups are present, and each R₁ group is independently selected from the group consisting of H, alkyl, alkoxy, and electron withdrawing groups, and each R₁ group located at any combination of the ortho-, meta-, and para-positions of the aryl ring. For example and without limitation, two R₁ groups may be present in a compound of formula (I) consistent with the present disclosure, and each R₁ group is independently selected from the group consisting of H, alkyl, alkoxy, and electron withdrawing groups. In other embodiments, three R₁ groups are present, and each R₁ group is independently selected from the group consisting of H, alkyl, alkoxy, and electron withdrawing groups. In still other embodiments, four R₁ groups are present. In other embodiments, five R₁ groups are present, and each R₁ group is independently selected from the group consisting of H, alkyl, alkoxy, and electron withdrawing groups.

When R₁ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

When R₁ is alkoxy, the alkoxy group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkoxy). The alkoxy group may be cyclic, in which case the alkoxy group may consist of three to six carbon atoms (i.e., C₃₋₆ alkoxy). The alkoxy group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

When R₁ is an electron withdrawing group, the electron withdrawing group may be a halogen, a halogenated alkyl group, or a halogenated alkoxy group. For example and without limitation, the electron withdrawing group may be a halogen, a halogen-substituted alkyl, a halogen-substituted alkoxyl, a perhaloalkyl, or a perhaloalkoxyl. fluoro, In some embodiments, each electron withdrawing group is independently selected from chloro, bromide, iodide, halomethyl, dihalomethyl, trihalomethyl, halomethoxyl, dihalomethoxyl, and trihalomethoxyl. In some embodiments, each electron withdrawing group is independently selected from the group consisting of fluoro, chloro, trifluoromethyl, and trifluoromethoxyl.

Each R₂ and R₃ are each independently H or alkyl or, taken together, form a 4- to 8-membered heterocyclic ring with the adjacent nitrogen atom. In some embodiments, R₂ is H while R₃ is alkyl. In some embodiments, both R₂ and R₃ are alkyl. When R₂ and/or R₃ are alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

In some embodiments, R₂ and R₃ are covalently connected to form, with the adjacent nitrogen atom, a heterocyclic ring. The heterocyclic ring may include one to three nitrogen atoms and a total of four to eight atoms in the ring. The heterocyclic ring may be unsubstituted or substituted, for example with an alkyl or alkoxyl group. For example and without limitation, R₂ and R₃ may be covalently connected and include a total of five carbon atoms to form a piperidinyl ring including the nitrogen atom adjacent to R₂ and R₃. In other embodiments, R₂ and R₃ may, together, have a general formula —(CH₂)_(p)N(R₇)(CH₂)q—, wherein p is 1 to 4, q is 1 to 4, p and q combined total 3 to 8, and R₇ is H or alkyl. When R₇ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₄ is H or alkyl. When R₄ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is H or one or more electron donating groups. When R₅ is one or more electron donating groups, R₅ may be a single electron donating group in the ortho-, meta-, or para-position of the aryl ring. In other embodiments, R₅ may be two to five electron donating groups in any combination of ortho-, meta-, and para-positions of the aryl ring. Each electron donating group may be independently selected from alkyl and alkoxyl. When R₅ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. When R₅ is alkoxyl, the alkoxy group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkoxy). The alkoxy group may be cyclic, in which case the alkoxy group may consist of three to six carbon atoms (i.e., C₃₋₆ alkoxy). The alkoxy group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

The number of methylene groups (n) in compounds of formula (I) may be 1 to 4. In some embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3. In other embodiments, n is 4.

Some example compounds of formula (I) are provided in Table 1 below.

TABLE 1 Example Compounds of Formula (I) Com- pound R₁ R₂ R₃ R₄ R₅ R₇ n p q 2290 H Me Me Me p-OMe n/a 2 n/a n/a 2291 m-Cl Me Me Me p-OMe n/a 2 n/a n/a 2292 m-Cl Me Me Me p-OMe n/a 2 n/a n/a p-Cl 2293 o-OMe Me Me Me p-OMe n/a 2 n/a n/a 2294 p-OMe Me Me Me p-OMe n/a 2 n/a n/a 2295 o-Me Me Me Me p-OMe n/a 2 n/a n/a 2296 m-OCF₃ Me Me Me p-OMe n/a 2 n/a n/a 2297 m-CF₃ Me Me Me p-OMe n/a 2 n/a n/a p-Cl 2298 2-Cl Me Me Me p-OMe n/a 2 n/a n/a 5-Cl 2299 m-Cl Me Me Me p-OMe n/a 2 n/a n/a p-F 2300 2-F Me Me Me p-OMe n/a 2 n/a n/a 3-Cl 2301 o-CF₃ Me Me Me p-OMe n/a 2 n/a n/a 2302 H H H Me p-OMe n/a 2 n/a n/a 2303 H —(CH₂)₅— Me p-OMe n/a 2 n/a n/a 2304 H —(CH₂)_(p)N(R₇) Me p-OMe Me 2 2 2 (CH₂)_(q)—

Referring now to FIG. 1 , compounds consistent with formula (I) can be synthesized by, for example, acylating anilines 8 _(I) with bromoacetyl bromide to form α-bromoamido intermediates 9 _(I). Intermediates 11 _(I) can be formed by alkylating anilines 10 _(I) with β-haloamines 12 _(I) in the presence of base. Combining intermediates 11 _(I) with the α-bromoamido intermediates 9 _(I) in the presence of base yields compounds of formula (I).

The present disclosure also provides compounds of formula (II):

wherein:

-   -   EWG is one or more electron withdrawing groups selected from the         group consisting of: Cl, F, halogenated alkyl, and halogenated         alkoxyl;     -   R₂ and R₃ are each independently H or alkyl;     -   Alk is an aliphatic carbon group consisting of 1 to 6 carbon         atoms; and     -   EDG is one or more alkoxy or alkyl electron donating groups.

In compounds of formula (II), EWG is one or more electron withdrawing groups each independently selected from the group consisting of: Cl, F, halogenated alkyl, and halogenated alkoxyl. For example and without limitation, EWG may in some embodiments be a single electron withdrawing group located at the ortho-, meta-, or para-position of the aryl ring. In other embodiments, EWG is two or more electron withdrawing groups located at any combination of the ortho-positions, the meta-positions, and the para-position of the aryl ring.

Each EWG may independently be selected from the group consisting of chloro, fluoro, halogenated alkyl, and halogenated alkoxyl. The halogenated alkyl may be monohaloalkyl, dihaloalkyl, trihaloalkyl, or perhaloalkyl and may have 1 to 6 carbon atoms (i.e., C₁₋₆ haloalkyl). The haloalkyl electron withdrawing group may be saturated or unsaturated. The halogenated alkyl may be branched, linear, or cyclic. In some embodiments, the electron withdrawing group is trifluoromethyl. The halogenated alkoxyl may be monohaloalkoxyl, dihaloalkoxyl, trihaloalkoxyl, or perhaloalkoxyl and may have 1 to 6 carbon atoms (i.e., C₁₋₆ haloalkoxyl). The haloalkoxyl electron withdrawing group may be saturated or unsaturated. The halogenated alkoxyl may be branched, linear, or cyclic. In some embodiments, the electron withdrawing group is trifluoromethoxyl.

Each R₂ and R₃ is independently H or alkyl. When R₂ and/or R₃ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Alk is an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

EDG is one or more alkoxy or alkyl electron donating groups. EDG may be a single electron donating group in the ortho-, meta-, or para-position of the aryl ring. In other embodiments, EDG may be two to five electron donating groups in any combination of ortho-, meta-, and para-positions of the aryl ring. Each EDG may be independently selected from alkyl and alkoxyl. When EDG is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. When EDG is alkoxyl, the alkoxy group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkoxy). The alkoxy group may be cyclic, in which case the alkoxy group may consist of three to six carbon atoms (i.e., C₃₋₆ alkoxy). The alkoxy group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. In some embodiments, EDG is para-alkoxy, such as para-methoxy, para-ethoxy, or para-propoxy.

Some example compounds of formula (II) are provided in Table 2 below.

TABLE 2 Example Compounds of Formula (II) Com- pound EWG R₂ R₃ Alk EDG R₇ n P q 2290 H Me Me Me p-OMe n/a 2 n/a n/a 2291 m-Cl Me Me Me p-OMe n/a 2 n/a n/a 2292 m-Cl Me Me Me p-OMe n/a 2 n/a n/a p-Cl 2293 o-OMe Me Me Me p-OMe n/a 2 n/a n/a 2294 p-OMe Me Me Me p-OMe n/a 2 n/a n/a 2295 o-Me Me Me Me p-OMe n/a 2 n/a n/a 2296 m-OCF₃ Me Me Me p-OMe n/a 2 n/a n/a 2297 m-CF₃ Me Me Me p-OMe n/a 2 n/a n/a p-Cl 2298 2-Cl Me Me Me p-OMe n/a 2 n/a n/a 5-Cl 2299 m-Cl Me Me Me p-OMe n/a 2 n/a n/a p-F 2300 2-F Me Me Me p-OMe n/a 2 n/a n/a 3-Cl 2301 o-CF₃ Me Me Me p-OMe n/a 2 n/a n/a 2302 H H H Me p-OMe n/a 2 n/a n/a 2303 H —(CH₂)₅— Me p-OMe n/a 2 n/a n/a 2304 H —(CH₂)_(p)N(R₇) Me p-OMe Me 2 2 2 (CH₂)_(q)—

Referring now to FIG. 2 , compounds consistent with formula (II) can be synthesized by, for example, acylating alkylanilines 8 _(II) with bromoacetyl bromide to form α-bromoamido intermediates 9 _(II). Intermediates 11 _(II) can be formed by alkylating anilines 10 _(II) with β-haloamines 12 _(II) in the presence of base. Combining intermediates 11 _(II) with the α-bromoamido intermediates 9 _(II) in the presence of base yields compounds of formula (II).

The present disclosure also provides compounds of formula (III):

wherein:

-   -   EWG is one or more electron withdrawing groups selected from the         group consisting of: Cl, F, CF₃, and OCF₃;     -   R₈ is selected from the group consisting of:         -   —NH₂, —N(H)Alk, —N(Alk)₂,

-   -   R₇ is H or alkyl;     -   m is 3 to 6;     -   p is 1 to 4;     -   q is 1 to 4;     -   p+q is3 to 6;     -   each Alk is independently an aliphatic carbon group consisting         of 1 to 6 carbon atoms; and     -   EDG is one or more alkoxy or alkyl electron donating groups.

In compounds of formula (III), EWG is one or more electron withdrawing groups each independently selected from the group consisting of: chloro, fluoro, trifluoromethyl, and trifluoromethoxy. For example and without limitation, EWG may in some embodiments be a single electron withdrawing group that is chloro, fluoro, trifluoromethyl, or trifluoromethoxy that is located at the ortho-, meta-, or para-position of the aryl ring. In other embodiments, EWG is two or more electron withdrawing groups independently selected from chloro, fluoro, trifluoromethyl, and trifluoromethoxy located at any combination of the ortho-positions, the meta-positions, and the para-position of the aryl ring.

R₈ is an n-amino substituent selected from —NH₂, —N(H)Alk, —N(Alk)₂,

When R₈ is —N(H)Alk or —N(Alk)₂, Alk is an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

When R₈ is

R₇ is H or alkyl. When R₇ is alkyl, the alkyl group can be an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be linear, branched, or cyclic. When the alkyl group is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. In some embodiments, R₇ is H. In other embodiments, R₇ is methyl. In other embodiments, R₇ is ethyl. In other embodiments, R₇ is propyl (e.g., n-propyl or isopropyl). In other embodiments, R₇ is butyl (e.g., 1-butyl, 2-butyl, or t-butyl). In other embodiments, R₇ is pentyl (e.g., 1-n-pentyl, 2-n-pentyl, 3-n-pentyl, 2-methylbut-4-yl, 2-methylbuty-3-yl, or 1-dimethylprop-1-yl). In other embodiments, R₇ is hexyl (e.g., 1-n-hexyl, 2-n-hexyl, 3-n-hexyl, 2-methylpent-5-yl, 2-methylpent-4-yl, 2-methylpent-3-yl, 3-methylpent-5-yl, 2-methylpent-1-yl, 2,3-dimethylbut-4-yl, 2,2-dimethylbut-4-yl, 3,3-dimethylbut-4-yl, 2,3,3-trimethylprop-3-yl, 1,1-dimethylbut-1-yl, or 1,2,2-trimethylbut-1-yl).

When R₈ is

m is 3 to 6. In some embodiments, m is 3, resulting in a 4-membered N-azetidinyl group. In other embodiments, m is 4, resulting in a 5-membered N-pyrrolidinyl group. In other embodiments, m is 5, resulting in a 6-membered N-piperidinyl group. In other embodiments, m is 6, resulting in a 7-membered N-azepanyl group.

When R₈ is

p is 1 to 4, q is 1 to 4, and p and q together total 3 to 6. For example and without limitation, p may be 1 while q is 2, 3, 4 or 5. Alternatively, p may be 2 while q is 1, 2, 3, or 4. In other embodiments, p is 3 while q is 1, 2, or 3.

EDG is one or more alkoxy or alkyl electron donating groups. EDG may be a single electron donating group in the ortho-, meta-, or para-position of the aryl ring. In other embodiments, EDG may be two to five electron donating groups in any combination of ortho-, meta-, and para-positions of the aryl ring. Each EDG may be independently selected from alkyl and alkoxyl. When EDG is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. When EDG is alkoxyl, the alkoxy group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkoxy). The alkoxy group may be cyclic, in which case the alkoxy group may consist of three to six carbon atoms (i.e., C₃₋₆ alkoxy). The alkoxy group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. In some embodiments, EDG is para-alkoxy, such as para-methoxy, para-ethoxy, or para-propoxy.

Some example compounds of formula (III) are provided in Table 3 below.

TABLE 3 Example Compounds of Formula (III) Compound EWG R₈ Alk EDG R₇ m n P q 2290 H —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2291 m-Cl —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2292 m-Cl —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a p-Cl 2293 o-OMe —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2294 p-OMe —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2295 o-Me —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2296 m-OCF₃ —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2297 m-CF₃ —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a p-Cl 2298 2-Cl —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 5-Cl 2299 m-Cl —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a p-F 2300 2-F —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 3-Cl 2301 o-CF₃ —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2302 H —NH₂ Me p-OMe n/a n/a 2 n/a n/a 2303 H

Me p-OMe n/a 5 2 n/a n/a 2304 H

Me p-OMe Me n/a 2 2 2

Referring now to FIG. 3 , compounds consistent with formula (III) can be synthesized by, for example, acylating alkylanilines 8 _(III) with bromoacetyl bromide to form α-bromoamido intermediates 9 _(III). Intermediates 11 _(III) can be formed by alkylating anilines 10 _(III) with β-haloamines 12 _(III) in the presence of base. Combining intermediates 11 _(III) with the α-bromoamido intermediates 9 _(III) in the presence of base yields compounds of formula (III).

The present disclosure further provides compounds of formula (IV):

wherein:

-   -   R₁ is H, Cl, F, —CF₃, —OCF₃, or —OMe;     -   R₈ is selected from the group consisting of:         -   —NH₂, —N(H)Alk, —N(Alk)₂,

-   -   R₇ is H or alkyl;     -   m is 3 to 6;     -   p is 1 to 4;     -   q is 1 to 4;     -   p+q is 3 to 6;     -   each Alk is independently an aliphatic carbon group consisting         of 1 to 6 carbon atoms; and     -   EDG is one or more amino, aryl, acylamido, acyloxy, alkoxy or         alkyl electron donating groups.

In compounds of formula (IV), R₁ is H or one or more substituents each independently selected from the group consisting of: chloro, fluoro, trifluoromethyl, trifluoromethoxy, and methoxy. For example and without limitation, R₁ may in some embodiments be a single substituent that is chloro, fluoro, trifluoromethyl, trifluoromethoxy, or methoxy that is located at the ortho-, meta-, or para-position of the aryl ring. In other embodiments, R₁ is two or more substituents each independently selected from chloro, fluoro, trifluoromethyl, trifluoromethoxy, and methoxy located at any combination of the ortho-positions, the meta-positions, and the para-position of the aryl ring.

R₈ is an n-amino substituent selected from —NH₂, —N(H)Alk, —N(Alk)₂,

When R₈ is —N(H)Alk or —N(Alk)₂, Alk is an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

When R₈ is

R₇ is H or alkyl. When R₇ is alkyl, the alkyl group can be an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be linear, branched, or cyclic. When the alkyl group is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. In some embodiments, R₇ is H. In other embodiments, R₇ is methyl. In other embodiments, R₇ is ethyl. In other embodiments, R₇ is propyl (e.g., n-propyl or isopropyl). In other embodiments, R₇ is butyl (e.g., 1-butyl, 2-butyl, or t-butyl). In other embodiments, R₇ is pentyl (e.g., 1-n-pentyl, 2-n-pentyl, 3-n-pentyl, 2-methylbut-4-yl, 2-methylbuty-3-yl, or 1-dimethylprop-1-yl). In other embodiments, R₇ is hexyl (e.g., 1-n-hexyl, 2-n-hexyl, 3-n-hexyl, 2-methylpent-5-yl, 2-methylpent-4-yl, 2-methylpent-3-yl, 3-methylpent-5-yl, 2-methylpent-1-yl, 2,3-dimethylbut-4-yl, 2,2-dimethylbut-4-yl, 3,3-dimethylbut-4-yl, 2,3,3-trimethylprop-3-yl, 1,1-dimethylbut-1-yl, or 1,2,2-trimethylbut-1-yl).

When R₈ is

m is 3 to 6. In some embodiments, m is ₃, resulting in a 4-membered N-azetidinyl group. In other embodiments, m is 4, resulting in a 5-membered N-pyrrolidinyl group. In other embodiments, m is 5, resulting in a 6-membered N-piperidinyl group. In other embodiments, m is 6, resulting in a 7-membered N-azepanyl group.

When R₈ is

p is 1 to 4, q is 1 to 4, and p and q together total 3 to 6. For example and without limitation, p may be 1 while q is 2, 3, 4 or 5. Alternatively, p may be 2 while q is 1, 2, 3, or 4. In other embodiments, p is 3 while q is 1, 2, or 3.

EDG is one or more amino, aryl, acylamido, acyloxy, alkoxy or alkyl electron donating groups. EDG may be a single electron donating substituent in the ortho-, meta-, or para-position of the aryl ring. In some embodiments, the single EDG substituent is at the ortho-position of the aryl ring. In other embodiments, the single EDG substituent is at the para-position of the aryl ring. In other embodiments, EDG may be two to five electron donating groups in any combination of ortho-, meta-, and para-positions of the aryl ring. In some embodiments, two EDG substituents are at the two ortho-positions of the aryl ring. In other embodiments, one EDG substituent is at the ortho-position and a second same or different EDG substituent is at the para-position of the aryl ring. In other embodiments, one EDG substituent is at one ortho-position of the aryl ring and a second same or different EDG substituent is at the other ortho-position of the aryl ring. In some embodiments, one EDG substituent is at one ortho-position of the aryl ring, a second same or different EDG substituent is at the other ortho-position of the aryl ring, and a third same or different EDG substituent is at the para-position of the aryl ring.

Each EDG may be independently selected from amino, aryl, acylamido, acyloxy, alkoxy or alkyl. When EDG is amino, the amino group may be —NH₂, —N(H)Alk, or —N(Alk)₂, with each Alk being an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. When EDG is aryl, the aryl substituent may be substituted or unsubstituted. The aryl substituent may be heteroatomic, such as a pyridine ring, a pyrazine ring, or a triazine ring that is substituted or unsubstituted. When EDG is acylamido, the acylamido group has a general formula of —N(H)COR₉, with R₉ being substituted or unsubstituted alkyl. When EDG is acyloxy, the acyloxy group has a general formula of —OC(O)R₉, with R₉ being substituted or unsubstituted alkyl. When EDG is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. When EDG is alkoxyl, the alkoxy group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkoxy). The alkoxy group may be cyclic, in which case the alkoxy group may consist of three to six carbon atoms (i.e., C₃₋₆ alkoxy). The alkoxy group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. In some embodiments, EDG is para-alkoxy, such as para-methoxy, para-ethoxy, or para-propoxy.

Some example compounds of formula (IV) are provided in Table 4 below.

TABLE 4 Example Compounds of Formula (IV) Compound R₁ R₈ Alk EDG R₇ m n p q 2290 H —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2291 m-Cl —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2292 m-Cl —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a p-Cl 2293 o-OMe —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2294 p-OMe —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2295 o-Me —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2296 m-OCF₃ —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2297 m-CF₃ —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a p-Cl 2298 2-Cl —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 5-Cl 2299 m-Cl —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a p-F 2300 2-F —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 3-Cl 2301 o-CF₃ —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2302 H —NH₂ Me p-OMe n/a n/a 2 n/a n/a 2303 H

Me p-OMe n/a 5 2 n/a n/a 2304 H

Me p-OMe Me n/a 2 2 2

Referring now to FIG. 4 , compounds consistent with formula (IV) can be synthesized by, for example, acylating alkylanilines 8 _(IV) with bromoacetyl bromide to form α-bromoamido intermediates 9 _(IV). Intermediates 11 _(IV) can be formed by alkylating anilines 10 _(IV) with β-haloamines 12 _(IV) in the presence of base. Combining intermediates 11 _(IV) with the α-bromoamido intermediates 9 _(IV) in the presence of base yields compounds of formula (IV).

The present disclosure provides compounds of formula (V):

wherein:

-   -   R₁ is H, Cl, F, —CF₃, —OCF₃, or —OMe;     -   R₈ is selected from the group consisting of:         -   —NH₂, —N(H)Alk, —N(Alk)₂,

-   -   R₇ is H or alkyl;     -   m is 3 to 6;     -   p is 1 to 4;     -   q is 1 to 4;     -   p+q is 3 to 6; and     -   each Alk is independently an aliphatic carbon group consisting         of 1 to 6 carbon atoms.

In compounds of formula (V), R₁ is H or one or more substituents each independently selected from the group consisting of: chloro, fluoro, trifluoromethyl, trifluoromethoxy, and methoxy. For example and without limitation, R₁ may in some embodiments be a single substituent that is chloro, fluoro, trifluoromethyl, trifluoromethoxy, or methoxy that is located at the ortho-, meta-, or para-position of the aryl ring. In other embodiments, R₁ is two or more substituents each independently selected from chloro, fluoro, trifluoromethyl, trifluoromethoxy, and methoxy located at any combination of the ortho-positions, the meta-positions, and the para-position of the aryl ring.

R₈ is an n-amino substituent selected from —NH₂, —N(H)Alk, —N(Alk)₂,

When R₈ is —N(H)Alk or —N(Alk)₂, Alk is an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

When R₈ is

R₇ is H or alkyl. When R₇ is alkyl, the alkyl group can be an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be linear, branched, or cyclic. When the alkyl group is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. In some embodiments, R₇ is H. In other embodiments, R₇ is methyl. In other embodiments, R₇ is ethyl. In other embodiments, R₇ is propyl (e.g., n-propyl or isopropyl). In other embodiments, R₇ is butyl (e.g., 1-butyl, 2-butyl, or t-butyl). In other embodiments, R₇ is pentyl (e.g., 1-n-pentyl, 2-n-pentyl, 3-n-pentyl, 2-methylbut-4-yl, 2-methylbuty-3-yl, or 1-dimethylprop-1-yl). In other embodiments, R₇ is hexyl (e.g., 1-n-hexyl, 2-n-hexyl, 3-n-hexyl, 2-methylpent-5-yl, 2-methylpent-4-yl, 2-methylpent-3-yl, 3-methylpent-5-yl, 2-methylpent-1-yl, 2,3-dimethylbut-4-yl, 2,2-dimethylbut-4-yl, 3,3-dimethylbut-4-yl, 2,3,3-trimethylprop-3-yl, 1,1-dimethylbut-1-yl, or 1,2,2-trimethylbut-1-yl).

When R₈ is

m is 3 to 6. In some embodiments, m is 3, resulting in a 4-membered N-azetidinyl group. In other embodiments, m is 4, resulting in a 5-membered N-pyrrolidinyl group. In other embodiments, m is 5, resulting in a 6-membered N-piperidinyl group. In other embodiments, m is 6, resulting in a 7-membered N-azepanyl group.

When R₈ is

p is 1 to 4, q is 1 to 4, and p and q together total 3 to 6. For example and without limitation, p may be 1 while q is 2, 3, 4 or 5. Alternatively, p may be 2 while q is 1, 2, 3, or 4. In other embodiments, p is 3 while q is 1, 2, or 3.

Alk is an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Some example compounds of formula (V) are provided in Table 5 below.

TABLE 5 Example Compounds of Formula (V) Compound R₁ R₈ Alk R₇ m n p q 2290 H —N(Alk)₂ Me n/a n/a 2 n/a n/a 2291 m-Cl —N(Alk)₂ Me n/a n/a 2 n/a n/a 2292 m-Cl —N(Alk)₂ Me n/a n/a 2 n/a n/a p-Cl 2293 o-OMe —N(Alk)₂ Me n/a n/a 2 n/a n/a 2294 p-OMe —N(Alk)₂ Me n/a n/a 2 n/a n/a 2295 o-Me —N(Alk)₂ Me n/a n/a 2 n/a n/a 2296 m-OCF₃ —N(Alk)₂ Me n/a n/a 2 n/a n/a 2297 m-CF₃ —N(Alk)₂ Me n/a n/a 2 n/a n/a p-Cl 2298 2-Cl —N(Alk)₂ Me n/a n/a 2 n/a n/a 5-Cl 2299 m-Cl —N(Alk)₂ Me n/a n/a 2 n/a n/a p-F 2300 2-F —N(Alk)₂ Me n/a n/a 2 n/a n/a 3-Cl 2301 o-CF₃ —N(Alk)₂ Me n/a n/a 2 n/a n/a 2302 H —NH₂ Me n/a n/a 2 n/a n/a 2303 H

Me n/a 5 2 n/a n/a 2304 H

Me Me n/a 2 2 2

Referring now to FIG. 5 , compounds consistent with formula (V) can be synthesized by, for example, acylating alkylaminoalkylphenols 8 _(V) with bromoacetyl bromide to form α-bromoamido intermediates 9 _(V). Intermediates 11 _(V) can be formed by alkylating anilines 10 _(V) with β-haloamines 12 _(V) in the presence of base. Combining intermediates 11 _(V) with α-bromoamido intermediates 9 _(V) in the presence of base yields compounds of formula (V).

The present disclosure provides compounds of formula (VI):

wherein:

-   -   R₁ is H, Cl, F, —CF₃, —OCF₃, —OMe, or methyl;     -   R₈ is selected from the group consisting of:         -   —NH₂, —N(H)Alk, —N(Alk)₂,

-   -   R₇ is H or alkyl;     -   m is 3 to 6;     -   p is 1 to 4;     -   q is 1 to 4;     -   p+q is 3 to 6; and     -   each Alk is independently an aliphatic carbon group consisting         of 1 to 6 carbon atoms.

In compounds of formula (VI), R₁ is H or one or more substituents each independently selected from the group consisting of: chloro, fluoro, trifluoromethyl, trifluoromethoxy, methoxy, and methyl. For example and without limitation, R₁ may in some embodiments be a single substituent that is chloro, fluoro, trifluoromethyl, trifluoromethoxy, or methoxy that is located at the ortho-, meta-, or para-position of the aryl ring. In other embodiments, R₁ is two or more substituents each independently selected from chloro, fluoro, trifluoromethyl, trifluoromethoxy, and methoxy located at any combination of the ortho-positions, the meta-positions, and the para-position of the aryl ring.

R₈ is an n-amino substituent selected from —NH₂, —N(H)Alk, —N(Alk)₂,

When R₈ is —N(H)Alk or —N(Alk)₂, Alk is an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl).

The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

When R₈ is

R₇ is H or alkyl. When R₇ is alkyl, the alkyl group can be an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be linear, branched, or cyclic. When the alkyl group is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. In some embodiments, R₇ is H. In other embodiments, R₇ is methyl. In other embodiments, R₇ is ethyl. In other embodiments, R₇ is propyl (e.g., n-propyl or isopropyl). In other embodiments, R₇ is butyl (e.g., 1-butyl, 2-butyl, or t-butyl). In other embodiments, R₇ is pentyl (e.g., 1-n-pentyl, 2-n-pentyl, 3-n-pentyl, 2-methylbut-4-yl, 2-methylbuty-3-yl, or 1-dimethylprop-1-yl). In other embodiments, R₇ is hexyl (e.g., 1-n-hexyl, 2-n-hexyl, 3-n-hexyl, 2-methylpent-5-yl, 2-methylpent-4-yl, 2-methylpent-3-yl, 3-methylpent-5-yl, 2-methylpent-1-yl, 2,3-dimethylbut-4-yl, 2,2-dimethylbut-4-yl, 3,3-dimethylbut-4-yl, 2,3,3-trimethylprop-3-yl, 1,1-dimethylbut-1-yl, or 1,2,2-trimethylbut-1-yl).

When R₈ is

m is 3 to 6. In some embodiments, m is ₃, resulting in a 4-membered N-azetidinyl group. In other embodiments, m is 4, resulting in a 5-membered N-pyrrolidinyl group. In other embodiments, m is 5, resulting in a 6-membered N-piperidinyl group. In other embodiments, m is 6, resulting in a 7-membered N-azepanyl group.

When R₈ is

p is 1 to 4, q is 1 to 4, and p and q together total 3 to 6. For example and without limitation, p may be 1 while q is 2, 3, 4 or 5. Alternatively, p may be 2 while q is 1, 2, 3, or 4. In other embodiments, p is 3 while q is 1, 2, or 3.

Some example compounds of formula (VI) are provided in Table 6 below.

TABLE 6 Example Compounds of Formula (VI) Compound R₁ R₈ Alk R₇ m n p q 2290 H —N(Alk)₂ Me n/a n/a 2 n/a n/a 2291 m-Cl —N(Alk)₂ Me n/a n/a 2 n/a n/a 2292 m-Cl —N(Alk)₂ Me n/a n/a 2 n/a n/a p-Cl 2293 o-OMe —N(Alk)₂ Me n/a n/a 2 n/a n/a 2294 p-OMe —N(Alk)₂ Me n/a n/a 2 n/a n/a 2295 o-Me —N(Alk)₂ Me n/a n/a 2 n/a n/a 2296 m-OCF₃ —N(Alk)₂ Me n/a n/a 2 n/a n/a 2297 m-CF₃ —N(Alk)₂ Me n/a n/a 2 n/a n/a p-Cl 2298 2-Cl —N(Alk)₂ Me n/a n/a 2 n/a n/a 5-Cl 2299 m-Cl —N(Alk)₂ Me n/a n/a 2 n/a n/a p-F 2300 2-F —N(Alk)₂ Me n/a n/a 2 n/a n/a 3-Cl 2301 o-CF₃ —N(Alk)₂ Me n/a n/a 2 n/a n/a 2302 H —NH₂ n/a n/a n/a 2 n/a n/a 2303 H

Me n/a 5 2 n/a n/a 2304 H

Me Me n/a 2 2 2

Referring now to FIG. 6 , compounds consistent with formula (VI) can be synthesized by, for example, acylating methylanilines 8 _(VI) with bromoacetyl bromide to form intermediates 9 _(VI). Intermediates 11 _(VI) can be formed by alkylating anilines 10 _(VI) with β-haloamines 12 _(VI) in the presence of base. Combining intermediates 11 _(VI) with intermediates 9 _(VI) in the presence of base yields compounds of formula (VI).

The present disclosure provides compounds of formula (VII):

wherein:

-   -   R_(1a) is H, Cl, F, —CF₃, —OMe, or methyl;     -   R_(1b) is H, Cl, F, —CF₃, or —OCF₃;     -   R_(1c) is H, Cl, F, or —OMe;     -   R_(1d) is H, Cl, F, —CF₃, or —OCF₃;     -   R_(1e) is H, Cl, F, —CF₃, —OMe, or methyl;     -   R₂ and R₃ are each independently H or alkyl or, taken together,         form a 4- to 8-membered heterocyclic ring with the adjacent         nitrogen atom;     -   R₄ is H or alkyl; and     -   R₅ is H or one or more electron donating groups.

In compounds of formula (VII), R_(1a) is H or an ortho-substituent selected from the group consisting of: chloro, fluoro, trifluoromethyl, methoxy, or methyl. R_(1b) is H or a meta-substituent selected from the group consisting of: chloro, fluoro, trifluoromethyl, or trifluoromethoxy. R_(1c) is H a para-substituent selected from the group consisting of: chloro, fluoro, or methoxy. R_(1d) is H or (e.g., when Rib is not H) a meta-substituent selected from the group consisting of: chloro, fluoro, trifluoromethyl, or trifluoromethoxy. R_(1e) is H or (e.g., when R_(1a) is not H) an ortho-substituent selected from the group consisting of: chloro, fluoro, trifluoromethyl, methoxy, or methyl. In some embodiments, R_(1a) is chloro, R_(1d) is chloro, and R_(1b), R_(1c), and R_(1e) are each H. In other embodiments, R_(1a) is fluoro, R_(1b) is chloro, and R_(1c), R_(1d), and R_(1e) are each H. In other embodiments, R_(1a) is trifluoromethyl, and R_(1b), R_(1c), R_(1d), and R_(1e) are each H. In other embodiments, R_(1a) is methoxy, and R_(1b), R_(1c), R_(1d), and R_(1e) are each H. In other embodiments, R_(1a) is methyl, and R_(1b), R_(1c), R_(1d), and R_(1e) are each H. In other embodiments, R_(1b) is chloro, R_(1c) is fluoro, and R₁a, R_(1d), and R_(1e) are each H. In other embodiments, R_(1b) is trifluoromethyl, R_(1c) is chloro, and R_(1a), R_(1d), and R_(1e) are each H. In other embodiments, R_(1b) is trifluoromethoxyl, and R_(1a), R_(1c), R_(1d), and R_(1e) are each H. In other embodiments, R_(1b) is chloro, R_(1c) is chloro, and R_(1a), R_(1d), and R_(1e) are each H. In other embodiments, R_(1b) is chloro, and R_(1a), R_(1c), R_(1d), and R_(1e) are each H. In other embodiments, R_(1c) is methoxyl, and R_(1a), R_(1b), R_(1d), and R_(1e) are each H.

Each R₂ and R₃ is independently H or alkyl. When R₂ and/or R₃ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

In some embodiments, R₂ and R₃ are covalently connected to form, with the adjacent nitrogen atom, a heterocyclic ring. The heterocyclic ring may include one to three nitrogen atoms and a total of four to eight atoms in the ring. The heterocyclic ring may be unsubstituted or substituted, for example with an alkyl or alkoxyl group. For example and without limitation, R₂ and R₃ may be covalently connected and include a total of five carbon atoms to form a piperidinyl ring including the nitrogen atom adjacent to R₂ and R₃. In other embodiments, R₂ and R₃ may, together, have a general formula —(CH₂)_(p)N(R₇)(CH₂)_(q)—, wherein p is 1 to 4, q is 1 to 4, p and q combined total 3 to 8, and R₇ is H or alkyl. When R₇ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. In some embodiments, R₂ and R₃ are both H. In other embodiments, R₂ and R₃ are both methyl. In still other embodiments, R₂ is H and R₃ is methyl.

R₄ is H or alkyl. When R₄ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is H or one or more electron donating groups. When R₅ is one or more electron donating groups, R₅ may be a single electron donating group in the ortho-, meta-, or para-position of the aryl ring. In other embodiments, R₅ may be two to five electron donating groups in any combination of ortho-, meta-, and para-positions of the aryl ring. Each electron donating group may be independently selected from alkyl and alkoxyl. When R₅ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. When R₅ is alkoxyl, the alkoxy group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkoxy). The alkoxy group may be cyclic, in which case the alkoxy group may consist of three to six carbon atoms (i.e., C₃₋₆ alkoxy). The alkoxy group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Some example compounds of formula (VII) are provided in Table 7 below.

TABLE 7 Example Compounds of Formula (VII) Com- pound R_(1x) R₂ R₃ R₄ R₅ R₇ n p q 2290 a-e: H Me Me Me p-OMe n/a 2 n/a n/a 2291 a: H Me Me Me p-OMe n/a 2 n/a n/a b: Cl c-e: H 2292 a: H Me Me Me p-OMe n/a 2 n/a n/a b: Cl c: Cl d-e: H 2293 a: OMe Me Me Me p-OMe n/a 2 n/a n/a b-e: H 2294 a-b: H Me Me Me p-OMe n/a 2 n/a n/a c: OMe d-e: H 2295 a: Me Me Me Me p-OMe n/a 2 n/a n/a b-e: H 2296 a: H Me Me Me p-OMe n/a 2 n/a n/a b: OCF₃ c-e: H 2297 a: H Me Me Me p-OMe n/a 2 n/a n/a b: CF₃ c: Cl d-e: H 2298 a: Cl Me Me Me p-OMe n/a 2 n/a n/a b-c: H d: Cl e: H 2299 a: H Me Me Me p-OMe n/a 2 n/a n/a b: Cl c: F d-e: H 2300 a: F Me Me Me p-OMe n/a 2 n/a n/a b: Cl c-e: H 2301 a: CF₃ Me Me Me p-OMe n/a 2 n/a n/a b-e: H 2302 a-e: H H H Me p-OMe n/a 2 n/a n/a 2303 a-e: H —(CH₂)₅— Me p-OMe n/a 2 n/a n/a 2304 a-e: H —(CH₂)_(p)N(R₇) Me p-OMe Me 2 2 2 (CH₂)_(q)—

Referring now to FIG. 7 , compounds consistent with formula (VII) can be synthesized by, for example, acylating anilines 8 _(VII) with bromoacetyl bromide to form intermediates 9 _(VII). Intermediates 11 _(VII) can be formed by alkylating anilines 10 _(II) with β-haloamines 12 _(VII) in the presence of base. Combining intermediates 11 _(VII) with intermediates 9 _(VII) in the presence of base yields compounds of formula (VII).

2. Anesthetic Compositions

The present disclosure provides compositions comprising a compound of any one of formulas (I) to (VII). In some embodiments, the compound is present in an amount effective to treat perceived pain or to prevent expected pain in a subject after the composition is applied to skin of the subject proximal to the perceived pain or the expected pain. In some embodiments, the compound is present in an amount of about 0.01% w/w to about 5% w/w, in an amount of about 0.05% w/w to about 2% w/w, or in an amount of about 0.1% w/w to about 1% w/w. In some embodiments, the compound is present in an amount of about 0.01% w/w, about 0.02% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w, about 0.07% w/w, about 0.08% w/w, about 0.09% w/w, about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, or about 5% w/w.

In some embodiments, the composition further comprises a carrier. In some embodiments, the carrier comprises, consists essentially of, or consists of water. In some embodiments, the carrier includes one or more solubilizing agents such as a hydrophobic solvent, an amphipathic solvent, a co-solvent, an emulsifier, a surfactant, etc.

In some embodiments, the composition further comprises a penetration enhancer, for example to enhance passage of the compound through skin of the subject. For example and without limitation, a composition of the present disclosure may include a vasodilator.

Compositions of the present disclosure may be in the form of a lotion, a cream, a gel, a stick, a spray, an ointment, or a paste. In some embodiments, the composition may be applied to skin of the subject using a dispenser. In other embodiments, the composition may be applied to skin of the subject using a dressing, a patch or a pad.

3. Methods of Treating or Preventing Pain

The present disclosure provides methods of treating or preventing pain in a subject. In some embodiments, the method comprises topically applying a composition of the present disclosure including a compound of any one of formulas (I) to (VII) to tissue (e.g., skin) of the subject. In some embodiments, the step of topically applying the composition occurs after the subject observes a pain sensation, and the composition is applied to tissue proximal to the observed pain sensation. In other embodiments, the step of topically applying the composition occurs before the subject observes a pain sensation, and the composition is applied to tissue proximal to a location where a pain sensation is expected to be observed by the subject.

EXAMPLES Example 1 Patch Clamp Testing

An examination of the in vitro effects of the compounds consistent with the present disclosure on ion channels Nav1.5 (a sodium voltage-gated channel alpha subunit found predominantly in cardiac muscle cells) and Nav1.7 (a sodium voltage-gated channel alpha subunit normally expressed in high levels in nociceptive pain neurons at dorsal root ganglion (DRG) and trigeminal ganglion and in sympathetic ganglion neurons) was performed using adult epithelial (ovarian) tissue CHO cells of Chinese hamsters (C. griseus) transformed with adenovirus 5 DNA and transfected with human ion channel cDNAs (ATCC, Manassas, VA; ChanTest Corp., Cleveland, OH). Cells were cultured in Ham's F-12 medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin G sodium, 100 μg/mL streptomycin sulfate, and 500 μg/mL G418 aminoglycoside antibiotic.

Each compound was analyzed at concentrations of 1000 μM, 300 μM, 100 μM, 30 μM, 10 μM, 3 μM, 1 μM, and 0.3 82 M. Lidocaine was included as a positive control at concentrations of 3000 μM, 1000 μM, 300 μM, 100 μM, 30 μM, 10 μM, 3 μM, and 1 μM. All tested compound formulations contained 0.3% DMSO. Each concentration of each compound was loaded into a well of a 384-well polypropylene compound plate using an automated liquid handling system (Integra Assist Plus, Integra) and then placed in the plate well of SyncroPatch 384PE (SP384PE; Nanion Technologies, Livingston, NJ) immediately before application of the cells.

Observed IC₅₀ values of the channel current inhibition for each test article are provided in Table 8 (Nav1.5 ion channel inhibition) and Table 9 (Nav1.7 ion channel inhibition).

TABLE 8 Inhibition of Nav1.5 Ion Channel IC₅₀, μM Compound TP1A TP2A TP25B 2290 >1000   >1000   >1000   2291    808.5    740.3    692.5 2292    207.7    215.7    193.1 2293 >1000   >1000   >1000   2294 >1000   >1000   >1000   2295 >1000   >1000   >1000   2296    254.4    235.9    221.6 2297     95.1     91.2     72.7 2298    249.4    240.3    204.0 2299    515.2    449.0    504.5 2300    327.2    307.0    259.2 2301    265.3    242.5    154.0 2302    124.1     96.8     75.9 2303     16.6     13.5      9.5 2304 >1000      880.4    670.2 Lidocaine    453.2     15.8     68.7 (pos. control) TP1A = Tonic Block TP2A = Inactivated State-Dependent Block TP25B = Use-Dependent Block

TABLE 9 Inhibition of Nav1.7 Ion Channel IC₅₀, μM Compound TP1A TP2A TP25B 2290 >1000   >1000   >1000   2291    561.4    463.1    490.4 2292    164.8    162.1    166.5 2293 >1000   >1000   >1000   2294 >1000   >1000   >1000   2295 >1000   >1000   >1000   2296    265.4    231.2    210.5 2297     74.7     66.2     54.4 2298    272.5    228.6    220.5 2299    392.6    315.0    334.3 2300    546.4    672.8    625.8 2301    312.1    275.3    235.0 2302     70.2     77.9     55.4 2303     15.0     14.5     13.1 2304 >1000   >1000   >1000   Lidocaine    407.8     23.7    112.7 (pos. control) TP1A = Tonic Block TP2A = Inactivated State-Dependent Block TP25B = Use-Dependent Block 

1. A compound of formula (VI):

wherein: R₁ is H, Cl, F, —CF₃, —OCF₃, —OMe, or methyl; R₈ is selected from the group consisting of: —NH₂, —N(H)Alk, —N(Alk)₂,

R₇ is H or alkyl; m is 3 to 6; p is 1 to 4; q is 1 to 4; p+q is 3 to 6; and each Alk is independently an aliphatic carbon group consisting of 1 to 6 carbon atoms.
 2. The compound of claim 1, wherein: R₁ is one or more of: H, meta-trifluoromethyl, meta-chloro, and para-chloro; and R₈ is —NH₂, N(H)Alk, N(Alk)₂,


3. The compound of claim 1, wherein: R₁ is methyl or methoxy; and R₈ is —NH₂, N(H)Alk, N(Alk)₂,


4. The compound of claim 1, wherein: R₁ is methyl; and R₈ is —NH₂, N(H)Alk, or N(Alk)₂.
 5. The compound of claim 1, wherein: R₁ is H, Cl, F, —CF₃, or —OCF₃; and R₈ is —NH₂, N(H)Alk, or N(Alk)₂.
 6. The compound of claim 1, wherein: R₁ is Cl, F, —CF₃, or —OCF₃; and R₈ is —NH₂, N(H)Alk, or N(Alk)₂.
 7. The compound of claim 1, wherein: R₁ is Cl, or F; and R₈ is —NH₂, N(H)Alk, or N(Alk)₂.
 8. The compound of claim 1 selected from the group consisting of:


9. The compound of claim 1, wherein the compound is:


10. The compound of claim 1, wherein the compound is:


11. The compound of claim 1, wherein the compound is:


12. The compound of claim 1, wherein the compound is:


13. The compound of claim 1, wherein the compound is:


14. The compound of claim 1, wherein the compound is:


15. The compound of claim 1, wherein the compound is:


16. The compound of claim 1, wherein the compound is:


17. The compound of claim 1, wherein the compound is


18. The compound of claim 1, wherein the compound is


19. The compound of claim 1, wherein the compound is


20. (canceled)
 21. A method of treating or preventing pain in a subject in need thereof, the method comprising administering to the subject a compound selected from the group consisting of: 